Multiple Sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that has many features suggesting autoimmune involvement. Experimental allergic encephalomyelitis (EAE) is an autoimmune disease animal model that has many clinical and histopathologic similarities with MS. EAE is mediated by CD4+ Th cells that recognize peptide determinants of myelin basic protein (MBP) or myelin proteolipid protein (PLP) in the CNS and initiate a cascade of events that leads to demyelination and paralysis. The molecular triad consisting of the class II molecule, the peptide target epitope, and the Th cell receptor (TCR) constitute the basic requirements for understanding activation and immunoregulation in autoimmune disease. Intervention of MBP-induced EAE has been achieved with immunospecific therapies aimed at each component of the trimolecular complex. However, recent evidence suggests that PLP may play an important and unique role in immunotherapy of autoimmune encephalomyelitis. Induction of tolerance in SJL/J mice to PLP but not MBP confers resistance to induction of EAE with whole spinal cord. Thus, specific immunotherapy with PLP appears to confer nonspecific protection against challenge with all spinal cord determinants. The recent availability of two distinctly different PLP determinants for SWR/J and SJL/J mice facilitates further studies on immunoregulation of PLP-induced EAE. Our goals in this investigation are: (1) to identify nonencephalitogenic analogues of both PLP determinants, (2) to determine the ability of nonencephalitogenic analogues to compete with the native sequence for class II or TCR binding sites, (3) to determine whether nonencephalitogenic analogues of PLP determinants can prevent EAE induction, and (4) to determine whether restricted TCR gene usage occurs in PLP-induced EAE and whether such restriction could provide a basis for specific immunotherapy. The results of these experiments could lead to a clearer understanding of autoimmune Th recognition and activation and may prove valuable in developing specific immunotherapy in MS once human encephalitogenic determinants are identified.